Glucose, a major source of energy for the body, is stored in the form of glycogen. It is later released with the help of enzymes. Glycogen is found mainly in liver and muscle cells, while the kidneys and intestines are minor storage sites. The underlying problem in all of the Glycogen Storage Diseases (GSD) is the use and storage of glycogen. Currently, there are about eleven known types of GSD that affect humans. All of the different types of GSD, also referred to as glycogenoses, result in the body not being able to produce sufficient glucose in the blood stream or to utilize glucose as a source of energy. Almost all forms of GSD occur when a child inherits the affected gene from both parents (autosomal recessive inheritance), each of whom is a carrier but may not be affected by GSD themselves.
Glycogen Storage Disease Type IV (also referred to as GSD IV, brancher deficiency, Andersen disease or amylopectinosis) represents 0.3% of all glycogenoses. In the human, it is a rapidly progressive disorder leading to terminal liver failure unless liver transplantation is performed. In Norwegian Forest Cats, GSD IV is fatal, primarily affecting striated muscles and the nervous system, while the liver remains relatively unaffected (Fyfe et al. 1992; Fyfe et al. 1994). A fatal neonatal disease closely resembling GSD IV has recently been reported in the American Quarter Horse, wherein clinical signs varied from stillbirth, transient flexural limb deformities, seizures, and respiratory or cardiac failure to persistent recumbency (Render et al. 1999; Valberg et al. 2001; Sponseller et al. 2002).
Thus, GSD IV is a clinically heterogeneous disorder. It is caused by a deficiency of the glycogen branching enzyme (GBE) (EC 2.4.1.18). The deficiency leads to an accumulation of glycogen having very long outer branches. This structurally abnormal glycogen is thought to trigger the body's immune system, causing the body to actually attack the glycogen and the tissues in which it is stored. Several mutations have been reported in the gene encoding human GBE, i.e., the GBE1 gene, in patients with the classic phenotype. Mutations in human GBE1 have also been identified in patients with the milder non-progressive hepatic form of the disease. The GBE amino acid sequence shows a high degree of conservation throughout species. Human GBE1 cDNA is approximately 3 Kb in length and encodes a 702-amino acid protein. The human GBE1 gene is located on chromosome 3p 14 and consists of 16 exons spanning at least 118 kb of chromosomal DNA.
In the Norwegian Forest cat, GSD IV is caused by a 6.1 kb deletion that eliminates exon 12 of the feline GBE1 gene (Fyfe et al. 1997).
Diagnosis of GSD IV is made on the basis of an individual's symptoms, the results of a physical examination and of biochemical tests. Occasionally, a muscle or liver biopsy is required to confirm the actual enzyme defect. GBE deficiency may be a common cause of neonatal mortality in Quarter Horses that is obscured by the variety of clinical signs that resemble other equine neonatal diseases. Therefore, despite the foregoing, there is a need in the art for additional diagnostic tests for diagnosing GSD IV in horses.